Physiologically active peptides such as hormone, cytokine, etc. have an important role in a living body, and it has frequently been carried out to use a physiologically active peptide itself as a medicine manufactured by mass production, or to use a physiologically active peptide as a medicine by structurally changing and modifying it by means of genetic engineering or protein synthesis.
However, the physiologically active peptide involves a risk that it is decomposed by digestive juices or enzymes in digestive tract or at the wall of the digestive tract when it is administered orally. Also, even when it is absorbed by the digestive tract, after the absorption, it circulates in the whole body after passing firstly through liver, so that there are problems that there is a possibility that it is decomposed in the liver (first-pass effect by the liver), and the physiologically active peptide with high hydrophilicity is a polymer and has high polarity whereby it is generally scarcely absorbed by a mucous membrane of the digestive tract.
Thus, to attain sufficient medicinal effects of the physiologically active peptide, it is not generally administered orally but is introduced in the form of injection subcutaneously, intramuscularly or directly into blood circulation. However, administration by an injection requires a patient's attendance at a hospital and is painful, so that the administration at home or without pain is desired.
As one of the administration form, it has been proposed to carry out nasal administration which is to administer a medicine to nasal mucous membrane (particularly, mucous membranes of concha nasalis superior, concha nasalis media, concha nasalis inferior) where epidermis cells having cilia covered by mucus, and basement membrane, and vascular system is developed at the bottom portion. However, the epidermis cells are closely bound by conjugant so that permeability of the physiologically active peptide having a large molecular weight, etc. is low and various preparations have been proposed to improve permeability.
For example, in Japanese Patent Publication No. Sho. 62-42888, there is described a composition for powdery preparation for nasal administration comprising physiologically active polypeptides and an agent (crystalline cellulose, etc.) which is water-absorbing and hardly water-soluble, and in Japanese Unexamined Patent Publication No. Hei. 8-27031, there is disclosed a composition for nasal absorption in which a physiologically active substance having a molecular weight of 40000 or less is uniformly dispersed, attached and bound to powdery or crystalline polyvalent metal compound carrier (aluminum compound, calcium compound, etc.) having an average particle diameter of 250 μm or less.
In summary collection of 27th Formulation Seminar of The Pharmaceutical Society of Japan, pp. 19-20, there has been reported that improvement in bioavailability through nasal administration had been observed when a hardly soluble powder such as calcium carbonate, ethyl cellulose, talc, barium sulfate, etc. had been used as a pharmaceutical carrier with regard to a water-soluble compound having a molecular weight of 1000 or more.
Also, in Japanese Unexamined Patent Publication No. Hei. 11-322582, a composition for nasal administration in which a medicine is uniformly dispersed and adsorbed on a primary granulated carrier of microcrystalline, etc. (calcium carbonate powder, etc.) having a number of cavities on the surface thereof has been disclosed.
Moreover, in Japanese Unexamined Patent Publication No. 2002-128704, there is described a nasal administration type preparation comprising a physiologically active substance, a carrier and an absorption promoter in living body (highly substituted hydroxypropyl cellulose, micro-crystalline cellulose), and as the carrier, a water-soluble polymer compound (cellulose derivatives such as crystalline cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, etc.) has been mentioned.
Also, in Japanese Unexamined Patent Publication No. Sho. 59-130820, an aqueous solution for nasal administration has been disclosed in which Polysorbate 80 which is a nonionic surfactant is added to calcitonin together with acetic acid and sodium acetate, and they are dissolved in purified water.
In Pharmaceutical Research, vol. 7, No. 7, pp. 772-776 (1990), there has been reported that when N-acetyl-L-cysteine, etc. are added with high concentrations to an aqueous buffer containing human growth hormone, and the preparation is nasally administered to rats, bioavailability is slightly improved.
However, these preparations for nasal administration have the problem that improvement in absorption is not sufficient.